Isospin Symmetry at High Spin Studied via Nucleon Knockout from Isomeric States.

One-neutron knockout reactions have been performed on a beam of radioactive ^{53}Co in a high-spin isomeric state. The analysis is shown to yield a highly selective population of high-spin states in an exotic nucleus with a significant cross section, and hence represents a technique that is applicable to the planned new generation of fragmentation-based radioactive beam facilities. Additionally, the relative cross sections among the excited states can be predicted to a high level of accuracy when reliable shell-model input is available. The work has resulted in a new level scheme, up to the 11^{+} band-termination state, of the proton-rich nucleus ^{52}Co (Z=27, N=25). This has in turn enabled a study of mirror energy differences in the A=52 odd-odd mirror nuclei, interpreted in terms of isospin-nonconserving (INC) forces in nuclei. The analysis demonstrates the importance of using a full set of J-dependent INC terms to explain the experimental observations.

Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes.

A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold found in several natural product families.

Development of GPIIb/IIIa antagonists as antithrombotic drugs.

Thrombosis represents a major target for development of drugs to prevent and treat a variety of cardiovascular and cerebrovascular diseases, which are the leading cause of morbidity and mortality in the Western world. This review by Andy Nichols and colleagues focuses on a central process in thrombosis, namely platelet aggregation, and how it can be inhibited by antagonists of the adhesion molecule GPIIb/IIIa. Successful and future therapeutic applications of GPIIb/IIIa antagonists, and their pharmacology, are considered in detail.

Conformationally constrained peptides and semipeptides derived from RGD as potent inhibitors of the platelet fibrinogen receptor and platelet aggregation.

Structure-activity studies have been pursued on cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-Pen]-NH2, 2 (SK&F 106760), a potent inhibitor of platelet aggregation, in an effort to improve potency and affinity for the GPIIb/IIIa receptor. Modifications on the N- and C-termini of 2 produced a series of peptides which indicate that the C-terminal carboxylate group may be a secondary receptor-binding element. Further modification by replacing the disulfide tether N alpha-acetylcysteine/penicillamineamide with the novel, inexpensive, achiral, constrained, and more lipophilic tether 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man) afforded the semipeptide cyclo-S,S-[Mba-(N alpha-Me)Arg-Gly-Asp-Man], 18 (SK&F 107260), which exhibited significant enhancement in both affinity and potency. To further investigate the effect of the phenyl ring at the C-terminus, peptides bearing the novel (2R,3S)- and (2R,3R)-beta-phenylcysteines were synthesized, which culminated in the cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-(2R,3S)-beta-phenylCys]-OH peptide, 22, which displayed substantial affinity and potency. We describe, herein, the development of both 18 and 22 and the additional structural modifications within the constrained cyclic disulfide ring to probe the stereochemical and steric requirements for receptor interaction.

Interactions between noradrenaline and alpha 2-adrenoceptor agonists in the superior mesenteric arterial bed of the rat.

Interactions between alpha 2-agonists and noradrenaline vasoconstrictor responses were studied in the superior mesenteric arterial bed of the rat by use of perfusion both in situ with blood and in vitro with Krebs-Henseleit solution. Xylazine (1.9 X 10(-6) mol) administered into the perfusion circuit reduced the maximum response to noradrenaline in the in situ preparation by 35% and decreased the pD50 for noradrenaline from 8.5 +/- 0.01 to 7.9 +/- 0.13 (n = 7). Yohimbine (1 mg kg-1, i.v.) gave a small parallel shift in the noradrenaline log dose-response curve and prevented the reduction in the maximum response by subsequent administration of xylazine. In vitro, xylazine (1.9 X 10(-6) mol) also gave a long-lasting reduction of 37% in the maximum response but did not affect the mid-point sensitivity to noradrenaline. Yohimbine (10(-6) M) did not change either of these effects. Clonidine (1.9 X 10(-6) mol) did not affect the maximum response to noradrenaline in vitro but did reduce the pD50 from 7.72 +/- 0.17 to 6.9 +/- 0.17 (n = 6). Yohimbine did not change these effects. Guanfacine (1.8 X 10(-6) mol) had no effect on the sensitivity of the in vitro preparation to noradrenaline but did reduce the maximum response by 20%. Yohimbine (10(-6)M) prevented the depression of the maximum response. It is concluded xylazine and clonidine interfere with noradrenaline induced vasoconstriction only to a limited extent through their interaction with alpha 2-adrenoceptors and that some other, as yet uncharacterized mechanism which may be activated by their aryl amidine structure, is responsible for their in vitro effects.

Cardiovascular responses in rats with glycerol-induced acute renal failure.

Autonomic and cardiovascular function were assessed in rats with glycerol-induced acute renal failure (ARF). Rats with ARF had significantly lower mean arterial blood pressure and heart rates and significantly elevated plasma noradrenaline concentrations. The chronotropic responses to right cervical sympathetic and vagal stimulation were diminished in rats with ARF. The pressor and depressor responses to noradrenaline and nitroprusside respectively when expressed as a change in mmHg pressure were significantly reduced in rats with ARF when compared to controls. However, when the depressor responses to nitroprusside were expressed as a percentage fall in basal mean arterial pressure, with the exception of the response to a dose of 10 micrograms kg-1, there were no significant differences between control and uraemic rats. The present findings show that in the rat, changes in cardiovascular responsiveness occur after a brief period of uraemia which are similar to those observed in patients and rats with chronic renal failure.

The effect of diltiazem on the coronary haemodynamic and cardiac functional effects produced by intracoronary administration of endothelin-1 in the anaesthetized dog.

1. We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary (i.c.) administration of endothelin-1 (ET-1) in anaesthetized dogs. 2. ET-1, 1, 3 and 10 ng kg-1 i.c., produced dose-related increases in coronary blood flow with no cardiac functional or systemic haemodynamic changes. ET-1, 30, 100 and 300 ng kg-1 i.c., produced dose-related reductions in coronary artery blood flow. The reduction in coronary blood flow was accompanied by dose-related falls in cardiac output, mean arterial pressure, +dP/dt and -dP/dt and increases in left ventricular end-diastolic pressure. However, there was no reflex tachycardia in response to the fall in blood pressure and at 300 ng kg-1, ET-1 produced a 22% reduction in heart rate. 3. Following a series of abnormal ECG changes, four out of five dogs died of ventricular fibrillation at 13 +/- 2 min after 300 ng kg-1 ET-1. 4. The administration of diltiazem (15 micrograms kg-1 min-1, i.v.) reduced mean arterial pressure by 10% and heart rate by 15%, and increased coronary blood flow by 39%. Diltiazem did not have any significant effect on the coronary dilator response to low doses of ET-1. Although there was a general trend for diltiazem to inhibit the coronary vasoconstrictor responses to ET-1, diltiazem significantly attenuated only the reduction in coronary blood flow produced by 100 ng kg-1 ET-1 by 60% but not the response to 30 or 300 ng kg-1 ET-1. Two out of five diltiazem-treated dogs died of ventricular fibrillation with a mean time to death of 20 min following treatment with ET-1 (300 kg- 1). 5. ET-1 is a very potent coronary vasodilator. At slightly higher doses ET-1 is also a coronary vasoconstrictor. ET-1 also appears to have direct cardiotoxicity independent of myocardial ischaemia. The vasoconstrictor activity and direct cardiotoxicity are only weakly inhibited by diltiazem.

Cardiovascular actions of a new selective postjunctional alpha-adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs.

1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.

The pharmacology of fenoldopam.

Fenoldopam is a selective dopamine1 (DA1) receptor agonist. Most of the DA1 receptor agonist activity of fenoldopam resides in the R-enantiomer, which also shows weaker alpha 2-adrenoceptor antagonist activity Fenoldopam produces vasodilation in vascular beds that are rich in vascular DA1 receptors, eg, renal and mesenteric receptors, and produces an increase in renal blood flow at doses that do not affect blood pressure. At higher doses, fenoldopam lowers blood pressure but still maintains renal perfusion. In addition to its renal vasodilator activity, fenoldopam is natriuretic, possibly resulting from a direct effect of DA1 receptors on the proximal convoluted tubule. In animals with spontaneous or drug-induced renal failure, fenoldopam improves renal function.

The relationship between alterations in alpha 1-adrenoceptor reserve by phenoxybenzamine and benextramine and the sensitivity of cirazoline-induced pressor responses to inhibition by nifedipine.

Nifedipine does not inhibit the alpha 1-adrenoceptor-mediated pressor response of cirazoline at a dose that significantly antagonizes the alpha 2-adrenoceptor-mediated pressor response of B-HT 933. After elimination of the alpha 1-adrenoceptor reserve with either phenoxybenzamine or benextramine, the response to cirazoline was rendered highly sensitive to antagonism by nifedipine. These results support the hypothesis that the resistance of alpha 1-adrenoceptor-mediated pressor responses to inhibition by calcium channel antagonists may be caused by a large alpha 1-adrenoceptor reserve.

Inhibition of plasma cholinesterase prevents the dopamine DA-1 receptor mediated renal vasodilation produced by ibopamine.

We have studied the dopamine DA-1 receptor mediated renal vasodilator response of the inotropic pro-drug, ibopamine, the diisobutyrate ester of epinine. In anesthetized dogs pretreated with phenoxybenzamine and propranolol to eliminate alpha- and beta-adrenoceptor mediated responses, respectively, ibopamine and epinine produced dose-dependent renal vasodilation. Treatment of animals with the cholinesterase inhibitor, physostigmine, markedly inhibited the renal vasodilation produced by ibopamine, but had no effect on the renal vasodilator response of epinine. We conclude that hydrolysis of ibopamine by plasma cholinesterase to yield epinine is necessary for the production of the dopamine DA-1 receptor mediated renal vasodilator response to ibopamine.

Differential effect of pertussis toxin on pre- and postjunctional alpha 2-adrenoceptors in the cardiovascular system of the pithed rat.

The role of the pertussis toxin-sensitive guanine nucleotide binding regulatory protein in pre- and postjunctional alpha 2-adrenoceptor-mediated responses has been investigated in the pithed rat. Pertussis toxin (50 micrograms/kg i.v., administered 3 days prior to experimentation) markedly inhibited the alpha 2-adrenoceptor-mediated vasopressor response to B-HT 933, but had no effect on the alpha 2-adrenoceptor-mediated cardiac neuroinhibitory effect of B-HT 933. Thus, postjunctional alpha 2-adrenoceptor activation in vascular smooth muscle, but not prejunctional alpha 2-adrenoceptor activation on sympathetic neurons, utilizes a pertussis toxin-sensitive guanine nucleotide binding regulatory protein.

Effects of chemical sympathectomy with 6-hydroxydopamine on cardiac output and its distribution in the rat.

Cardiac output and its regional distribution were determined with radioactive microspheres in pentobarbitone anaesthetised rats 16 h and 5 days after sympathectomy with 6-hydroxydopamine (150 mg/kg i.p. over 24 h). Distribution was not different at either time in sympathectomised animals compared to controls given i.p. saline/ascorbic acid. Cardiac output was 12% greater 16 h after sympathectomy than in the controls but heart rate and blood pressure were 20% lower. Stroke volume was 43% greater in animals given 6-hydroxydopamine and total peripheral resistance 29% lower than in sham-sympathectomised rats. Five days after sympathectomy, blood pressure and heart rate were still lower in sympathectomised rats, but cardiac output and total peripheral resistance were not significantly different from control. It is concluded that basal sympathetic tone does not determine the distribution of cardiac output at rest and that its primary effect on the heart is to maintain heart rate rather than contractility.

Effects of benzylic hydroxyl substitution on the alpha-adrenoceptor blocking activity of tolazoline.

The R(-)- and S(+)-enantiomers of alpha-hydroxytolazoline, the benzylic hydroxy-substituted derivative of the alpha-adrenoceptor antagonist, tolazoline, were evaluated at alpha 1- and alpha 2-adrenoceptors in canine saphenous vein. Benzylic hydroxyl substitution of tolazoline in either the R(-) or S(+) configuration significantly decreased affinity at both alpha 1- and alpha 2-adrenoceptors. Differences in affinity between the R(-)- and S(+)-enantiomers were small, which is characteristic of imidazolines, but in marked contrast to phenethylamines where enantiomeric differences are large. The rank order of affinities at alpha 1- and alpha 2-adrenoceptors is tolazoline greater than S(+)-alpha-hydroxytolazoline = R(-)-alpha-hydroxytolazoline, which is different from that order predicted by the Easson-Stedman hypothesis (i.e., R(-) greater than S(+) = desoxy). The findings support our contention that phenethylamines and imidazolines interact differently with alpha-adrenoceptors.

The in vitro pharmacological profile of SK&F 106760, a novel GPIIB/IIIA antagonist.

The properties of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methyl-arginyl-glycyl-aspartyl-penicillamine-amide] as a GPIIb/IIIa antagonist have been studied in vitro and compared with those of the parent molecule, Ac-RGDS-NH2. Ac-RGDS-NH2 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 530 +/- 73 nM. In canine platelet rich plasma Ac-RGDS-NH2 produced a concentration related inhibition of adenosine diphosphate-induced platelet aggregation following preincubation for 3 min with an IC50 of 91 +/- 1 microM. However, incubation in platelet rich plasma for 3 hr abolished the activity of Ac-RGDS-NH2. SK&F 106760 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 477 +/- 57 pM. SK&F 106760 inhibited adenosine diphosphate-induced platelet aggregation in human platelet rich plasma with an IC50 of 230 +/- 60 nM but did not inhibit the von Willebrand Factor receptor (GPIb/IX)-mediated platelet agglutination produced by ristocetin. In canine platelet rich plasma SK&F 106760 inhibited aggregation produced by adenosine diphosphate, collagen and epinephrine/U-46619 with IC50 values of 355 +/- 35, 260 +/- 20, and 490 +/- 90 nM, respectively and in gel filtered platelets inhibited thrombin-mediated aggregation with an IC50 of 188 +/- 10 nM. Preincubation of SK&F 106760 in platelet rich plasma for three hours had no significant effect on its ability to inhibit adenosine diphosphate-induced platelet aggregation. SK&F 106760 produced insurmountable inhibition of adenosine diphosphate-induced platelet aggregation in the presence of constant fibrinogen concentrations, but produced competitive inhibition of the concentration-response curve to fibrinogen in adenosine diphosphate-activated platelets with a Kb of 8.0 +/- 1.0 nM. Thus, SK&F 106760 is a potent, stable competitive GPIIb/IIIa antagonist with no detectable activity at the von Willebrand Factor receptor (GPIb/IX).

Comparison of the effects of intravenous and intrasplenic infusions of glucagon on cardiac output and its distribution in the rat.

In order to determine whether or not glucagon released from the pancreas might have local vascular effects, the actions upon regional haemodynamics in the anaesthetised rat of two doses of glucagon (2 and 10 micrograms kg-1 min-1) infused intrasplenically (and thus into the portal vein) were compared with those of a single dose (2 micrograms kg-1 min-1) infused i.v. Infusion of glucagon i.v. produced a significantly increased heart rate (by 6%) and cardiac output (by 23%) in the experimental animals compared to those receiving saline by the same route. Total peripheral resistance fell by 24%. A greater proportion of the cardiac output passed to the coronary and renal vascular beds and blood flow was increased in the spleen, testes, pectoral skeletal muscle, stomach and small intestine as well as the heart and kidneys. The lower dose infused intrasplenically had no significant effect on cardiac output or total peripheral resistance but significantly increased the proportion of cardiac output passing both to the stomach and the small intestine such that the percentage of cardiac output flowing through the portal vein increased from 19.1 +/- 1.1% to 23.8 +/- 1.7%. Intrasplenic infusion of 10 micrograms kg-1 min-1 significantly increased cardiac output (by 29%) but reduced total peripheral resistance by 37%. Greater fractions of the cardiac output were received by the spleen, small intestine and epididymides. Blood flow was increased in these organs and the skin, kidneys, stomach, large intestine and the mesentery. It is concluded that pharmacologically effective amounts of glucagon only passed into the systemic circulation with the higher dose infused intrasplenically.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologic differentiation between pre- and postjunctional alpha 2-adrenoceptors by SK&F 104078.

Most alpha 2-adrenoceptor antagonists do not discriminate between pre- and postjunctional alpha 2-adrenoceptors, and this has led to the commonly held belief that pre- and postjunctional alpha 2-adrenoceptors may represent one homogeneous population of receptors. SK&F 104078 has been shown to be a potent antagonist at postjunctional alpha 2-adrenoceptors at concentrations that do not block prejunctional alpha 2-adrenoceptors. Thus, SK&F 104078 is a competitive postjunctional alpha 2-adrenoceptor antagonist in canine and rabbit saphenous veins, canine saphenous artery and human platelet with a dissociation constant of approximately 100 nmol/l. Conversely, SK&F 104078 is inactive as a prejunctional alpha 2-adrenoceptor antagonist in atria from dog, guinea pig, rabbit and rat, and in guinea-pig ileum at concentrations up to 10,000 nmol/l. Likewise, SK&F 104078 has the ability to block postjunctional arterial alpha 2-adrenoceptors in vivo in the pithed rat at doses that do not inhibit prejunctional alpha 2-adrenoceptors in the same model. The results suggest that pre- and postjunctional alpha 2-adrenoceptors may not represent one homogeneous class, but rather are discrete subtypes of the alpha 2-adrenoceptor that may be differentiated by SK&F 104078.

Metabolic regulation by alpha 1- and alpha 2-adrenoceptors.

The role of alpha-adrenoceptors in the mediation of autonomic function, particularly in the control of the cardiovascular system, is widely known. However, alpha-adrenoceptors are also important in the regulation of a variety of metabolic processes that occur in the body either through direct action or by stimulation of the release of other mediators that control metabolic function. Thus, alpha 2-adrenoceptor activation by circulating or neuronally released catecholamines inhibits the release of insulin from pancreatic islet beta-cells and, by inhibiting this response, alpha 2-adrenoceptor antagonists have been shown to have an antihyperglycemic effect. The alpha-adrenoceptor-mediated regulation of the release of pituitary hormones is indirect, with alpha-adrenoceptors being located on peptidergic neurons in the hypothalamus that secrete releasing hormones into the hypophysial portal system to regulate the secretion of hormones from the anterior pituitary gland. Thus, the increase in cortisol secretion from the adrenal glands following a meal is produced, at least in part, by an alpha 1-adrenoceptor-mediated increase in vasopressin and CRF-41 secretion from neurons on the hypothalamus that stimulate the release of adrenocorticotrophic hormone secretion from the pituitary gland, which subsequently stimulates the synthesis and release of cortisol from the adrenal medulla. In addition to metabolic regulation by alpha 1- and alpha 2-adrenoceptors within the endocrine system, alpha-adrenoceptors are also a component of the system that regulates certain aspects of metabolism within autonomic effector cells, such as the control of smooth muscle cell division and growth during periods of continued alpha-adrenoceptor activation as a result of activation of second messenger systems.